• Journal of Korean Society of Occupational and Environmental Hygiene
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• v.19 no.1
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• pp.73-79
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• 2009

This study was undertaken to investigate the effects of single and combined exposure of toluene (T) and xylene (X) on the cytochrome-450(CYP)-mediated metabolizing capacity, induction of CYP isozymes and the excretion of their metabolites in urine. Animal were adults male Sprague-Dawley (SD) rats and divided into 4 groups such as control, T (treated with 63.7 mg/body kg), X (treated with 65.9 mg/body kg) and TX(T=X). Organic solvents was administrated by intraperitoneal injection for 3 days. The contents of protein and CYP in liver microsomes of control group were $16.48{\pm}0.56 mg/m{\ell}$ and $0.744{\pm}0.025$ nmol/mg protein, respectively, and they contents were significantly lower than in derived from treated groups (p<0.01). The activities of PROD and ${\rho}NPH$ were significantly higher in single treated groups than in control and combined group (TX). When Western immunoblotting were carried out with two monoclonal antibodies (MAb 1-98-1 and MAb 2-66-3) which were specific against CYP2B1/2 and CYP2E1, respectively, a strong signal corresponding to CYP2B1/2 was observed in microsomes obtained from rats treated with X and TX. The color density against CYP2E1 was slightly increased in T and TX groups compared with C and X groups. The amounts of urinary hippuric acid in T single treated group was $3.29{\pm}1.97$ g/g creatinine and TX combined group was $2.91{\pm}1.76$ g/g creatinine, but was not significant. However, amount of urinary methy hippuric acid in X single treated group ($1.62{\pm}0.72$ g/g creatinine) was significantly higher than TX combined group ($0.93{\pm} 0.63$ g/g creatinine)(p<0.01). These results suggested that CYP2E1 isozyme might be responsible for the metabolism of T, and CYP2B1/2 isozyme is for X. And also, difference of metabolites level between single and combined group may be speculated that the intermediates of T and X interacted each other in the process of their metabolite formation reaction.

• Journal of the Korean Society of Food Science and Nutrition
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• v.25 no.6
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• pp.969-975
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• 1996

The purpose of this study was to investigate the effect of dietary vitamin E on microsomal mixed function oxidase system of liver and lung in streptozotocin(STZ) induced diabetic rats. Sprague-Dawley male rats weighing 140 $\pm$ 10mg were randomly assigned to one control and three STZ-diabetic groups. Diabetic groups were divided into DM-0E(vitamin E free diet), DM-40E(40mg vitamin E kg/diet) and DM-400E(400mg vitamin E kg/diet) according to the level of vitamin E supplementation. Diabetes was experimentally induced by intravenous administration of 55mg/kg b.w of STZ in citrate buffer(pH 4.3) after 4 week feeding of three experimental diets. Animals were sacrificed at the 6th day of diabetic state. The contents of cytochrome P$_{450}$ in DM-0E, DM-40E and DM-400E groups of liver were increased by 162%, 150% and 56%, respectively, compared with that of control. Also the contents of cytochrome P$_{450}$ in lung were similar to liver. The activities of cytochrome bs in DM-0E and DM-40E groups of the liver were increased by 70% and 53%, respectively, compared with that of control, but not in DM-400E group. The activities of bs in DM-0E, DM-40E and DM-400E groups of lung were signficantly increased. Activity of cytochrome P$_{450}$ reductase in DM-0E, DM-40E of liver and lung were higher than that of control group, but the activity of DM-400E group was not different from that of control. The lipid peroxide values of DM-0E, DM-40E and DM-400E groups were 143%, 95% and 31% higher than those of control. It was concluded that dietary vitamin E had protective effects on lipid peroxidation accompanied with increased mixed function of oxidase activity in diabetic rats.

• YAKHAK HOEJI
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• v.43 no.6
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• pp.827-833
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• 1999

In this study, we have investigated the effect of Biphenyl Dimethyl Dicarboxylate (DDB), a synthetic analogue of Schizandrin C isolated from Schizandrae Fructus on cytochrome $P_450$ lAl and 2Bl, and the protective mechanism against $CCl_4-induced$ hepatotoxicity in rat liver. After DDB was administered into male rats for different periods of time (1~7 days) and with different doses (25, 50, 100 and 200 mg/kg), mRNA levels of CYPlAl were measured by polymearse chain reaction (PCR) and assayed the activities of CYPlAl specific ethoxyresorufin-O-dealkylase (EROD) and CYP2Bl specific benzyloxyresorufin-O-dealkylase (BROD). DDB treatment resulted in increase in CYP2Bl mRNA level and BROD activity, whereas there was no change in CYPlAl mRNA level and EROD activity. This effect of DDB was time-and dose-dependent and reached maximal level by 3 day and 200 mg/kg treatment. In addition, rats were pre-treated with DDB at doses of 25, 50 or 100 mg/kg daily for 4 days, 3-hr after final treatment on the 4th day, $CCl_4$ 0.3ml/kg was intraperitonially injected into the rats to examine the effect of DDB on $CCl_4-induced$ hepatic injury. Serum levels of ALT and AST were determined and histopathological examination was done in rat liver. Furthermore, we have measured hepatic microsomal malondialdehyde(MDA) level, a parameter of lipid peroxidation. Based on serum ALT level and lipid peroxidation, pretreatment of DDB, 50 mg/kg appeared the most protective effect against $CCl_4-induced$ heapatotoxity. These results indicate that DDB stimulates CYP2Bl mRNA level and BROD activity in time and dose dependent manner and suggest that protective effect of DDB on $CCl_4-induced$ hepatotoxicity may be mediated through free radical scavenging.

• Archives of Pharmacal Research
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• v.26 no.5
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• pp.394-404
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• 2003

Certain polycyclic aromatic hydrocarbons (PAHs) have been reported to induce cytochrome P450 (CYP) 1A1 and 1A2. In the present study, the effects of six well-known PAHs, such as benzo[a]pyrene, benz[a]anthracene, dibenz[a,h]anthracene, chrysene, benzo[k]fluorancene and benzo[b]fluorancene, on the activities of hepatic and pulmonary CYP enzymes were investigated in male ICR mice. When mice were treated intraperitoneally with 3, 10 and 30 mg/kg of individual PAHs for 3 consecutive days, the activities of ethoxyresorufin- and methoxyresorufin-Ο-dealkylases were significantly and differentially induced in both liver and lung. Moreover, other CYP isozyme-associated monooxygenase activities were also induced significantly in liver and lung with characteristic induction profiles. Our present results suggest that individual PAHs might have inductive effects on CYP isozymes, and that the characteristic inductive effects of individual PAHs on certain CYP isozymes would be developed as a marker for determining exposure to certain PAHs.

• Journal of Haehwa Medicine
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• v.8 no.1
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• pp.643-657
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• 1999

Through observing effect of BOPEASAN(BPT) on an aging white rat's metabolic enzyme system, the following conclusions were addressed 1. The quantity of the lipid peroxide in lung of was decreased meaningfully in all of experimental subject groups, relatively to counterpart groups. 2. Cytochrome P-450, Cytochrome b5, NADPH-Cytochrome P45, was decreased meaningfully in the experimental subject groups B,C and D. 3. superoxide dismutase, catarase, grutathione peroxidase, was increased meaningfully in the experimental subject groups B.C and D. 4. glutathione, glutathione S-transferase, glutathione redutase, ${\gamma}$-Glutamylcytein synthetase, had no meaningful change in the experimental subject groups. Regarding the above conclusions, the Bopeasan was affecting positively on both lipid peroxide a nd the enzyme system, as well as it has efficacy of suppressing the phenomena of aging, Therefore, the Bopeasan is, hereafter, expected to be applied clinically.

• YAKHAK HOEJI
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• v.41 no.4
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• pp.492-497
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• 1997

A difference in ethanol metabolism between premature and young adult rats was examined. Female SD rats, either 4wk or 12wk old, were injected with a single dose of ethanol (1.5g /kg) through jugular vein and the blood ethanol level was monitored for 300 min using a gas chromatographic method. Reduction of blood ethanol level per unit of time was less and the area under the blood concentration-time curve (AUC) was significantly greater in young adults compared to premature rats. Activity of hepatic alcohol dehydrogenase was not influenced by the age increase. Total cytochrome P-450, cytochrome $b_5$. or aminopyrine N-demethylation was not different between premature rats and young adult rats. However, p-nitrophenol hydroxylation and p-nitroanisole O-demethylation activities were significantly higher in premature rats. The relative liver weight was 45% greater in premature rats leading to an overall increase in ethanol metabolizing activity in these animals. The results indicate that the reduction in ethanol elimination in young adult rats appears to be mostly associated with the decrease in relative liver weight as the age of animals increases.

• YAKHAK HOEJI
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• v.44 no.4
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• pp.300-307
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• 2000

Expression of xenobiotic-metabolizing enzymes can be altered by xenobiotics, which represents changes in the production of reactive metabolic intermediates as well as toxicities in tissues. Metabolic intermediates derived from xenobiotics are considered to produce the reactive oxygen species including drug free radicals and hydroxyl free radicals, which would be ultimately responsible for drug-induced toxicities. The effects of 1,2-benzothiazine anti-inflammatory agents on the expression of xenobiotic-metabolizing enzymes including major cytochrome P450s, microsomal epoxide hydrolase (mEH) and glutathione S-transferase (GST) were studied in the liver with the aim of providing the part of information on potential production of reactive metabolites and hepatotoxicity by the agents. The synthetic compounds 24, 36 and 39 exhibited anti-inflammatory effects in rats as assessed by the Randall-Selitto method. The anti-inflammatory effect was detected as early as at 30 min after gavaging the agents with the ED5O being noted at 80 mg/kg, which was comparable to that of ibuprofen. Treatment of rats with each compound (100 mg/kg, 3d) resulted in no significant induction in the immunochemically-detectable cytochromes P45O 1A1/2, P450 2B1/2, P45O 2 Cl1 and P45O 2El. Changes in the mEN expression were also minimal, as evidenced by both Western blot and Northern blot analyses. Hepatic GST expression was slightly increased by the agents: GST Ya protein and mRNA expression was ～1.5-fold increased after treatment with compounds 24 and 39, whereas GST Yb1/2 and Yc1/2 mRNA levels were elevated 2- to 3-fold. In summary the effects of the synthetic 1,2-benzothiazines on the expression of major P45O, mEH and G57 were not significant, providing evidence that metabolic activation of the agents, potential drug interaction and hepatotoxicity would be minimal.

• Mass Spectrometry Letters
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• v.12 no.4
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• pp.172-178
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• 2021

HYIpro-3-1 is an adjuvant for preventing or treating inflammatory growth diseases. In this study, we identified the metabolic pathway of HYIpro-3-1 in human liver microsomes (HLMs) by quadrupole-orbitrap high-resolution mass spectrometry (HR-MS) and characterized the major human cytochrome P450 (CYP). Ten metabolites were identified, including one O-demethylation (M1), two O-demethylation and monohydroxylation (M2 and M3), and seven monohydroxylation metabolites (M4-M10). Based on the HR-MS² spectra, the metabolites are divided into two groups of monohydroxylated metabolites according to the hydroxylation position. We verified that HYIpro-3-1 is metabolized by CYP in HLMs, CYP2B6 is mainly involved in O-demethylation, and various CYPs are involved in the monohydroxylation of HYIpro-3-1.

• Journal of Haehwa Medicine
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• v.8 no.1
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• pp.625-641
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• 1999

Aging occurs as a part of maturation as the time progresses which manifests in the human body causing morphological and functional degeneration, eventually leading to death. This experimental study was conducted to investigate a herbal formula to fortify the heart with easy clinical applications. Sungshimsan was chosen to study its effects in heart lipid peroxide and metabolic enzyme system in senescence induced rats. After pre-treatment of Sungshimsan for 2 weeks at the dosage of A (100mg/kg), B (250mg/kg), C (350mg/kg), and D (500mg/kg), a lipid peroxide and metabolic enzyme system changes of the heart were meaured in 32 weeks old rats. The following results were obtained in this study: 1. The contents of lipid peroxide was significantly reduced in the experimental groups treated with greater than 2 weeks at 250mg/kg. 2. The enzymatic activity of cytochrome P-450, cytochrome b5, and NADPH-cytochrome P450 reductase were significantly decreased in the 250mg/kg, 350mg/kg, and 500mg/kg experimental groups. 3. The activity of glutathione and glutathione S-transferase were significantly increased in the 250mg/kg, 350mg/kg, and 500mg/kg experimental groups. 4. The activity of glutathione reductase and glutathione peroxidase were not influenced compared to the control group. 5. The activity of ${\gamma}$-glutamylcystein synthetase was significantly increased in the 250mg/kg, 350mg/kg, and 500mg/kg experimental groups. 6. The activity of enzymes detoxificatioon superoxide dismutase and catalase were not influenced compared to the control group. Summarizing above results suggest that the Sungshimsan has profound effects in the heart lipid peroxide, free radicals, and delaying the heart aging process. Further clinical researches and application can be anticipated on the topic of senility and gerontology.

• Archives of Pharmacal Research
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• v.27 no.7
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• pp.781-789
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• 2004

The effect of 1,8-cineole on cytochrome P450 (CYP) expression was investigated in male Sprague Dawley rats and female BALB/c mice. When rats were treated orally with 200, 400 and 800 mg/kg of 1,8-cineole for 3 consecutive days, the liver microsomal activities of benzy-loxyresorufin- and pentoxyresorufin-D-dealkylases and erythromycin N-demethylase were dose-dependently induced. The Western immunoblotting analyses clearly indicated the induction of CYP 2B1/2 and CYP 3A1/2 proteins by 1,8-cineole. At the doses employed, 1,8-cineole did not cause toxicity, including hepatotoxicity. Subsequently, 1,8-cineole was applied to study the role of metabolic activation in thioacetamide-induced hepatotoxicity and/or immunotoxicity in animal models. To investigate a possible role of metabolic activation by CYP enzymes in thioacetamide-induced hepatotoxicity, rats were pre-treated with 800 mg/kg of 1,8-cineole for 3 days, followed by a single intraperitoneal treatment with 50 and 100 mg/kg of thioacetamide in saline. 24 h later, thioacetamide-induced hepatotoxicity was significantly potentiated by the pretreatment with 1,8-cineole. When female BALB/c mice were pretreated with 800 mg/kg of 1,8-cineole for 3 days, followed by a single intraperitoneal treatment with 100 mg/kg of thioace-tamide, the antibody response to sheep red blood cells was significantly potentiated. In addition, the liver microsomal activities of CYP 2B enzymes were significantly induced by 1,8-cineole as in rats. Taken together, our results indicated that 1,8-cineole might be a useful CYP modulator in investigating the possible role of metabolic activation in chemical-induced hepato-toxicity and immunotoxicity.